Role of Promoter C-480T Polymorphism of Hepatic Lipase in the Development of Atherosclerosis

Abstract

Atherosclerosis is the major cause of morbidity and mortality in Western society. Atherosclerosis arises from a genetic predisposition, interacting with environmental risk factors. Hepatic lipase (HL) is a glycoprotein, functioning mainly as a lipolytic enzyme by hydrolysing triglycerides and phospholipids in almost all major classes of lipoproteins. HL maybe involved in the modulation of the risk for dyslipidemia and atherosclerosis due to its essential role in both high-density lipoprotein (HDL) and triglyceride-rich lipoprotein metabolism. The HL gene (LIPC) has a functional promoter polymorphism at position -480, which affects transcription and leads to CC, CT and TT genotypes.

To elucidate the association betweem LIPC C-480T genotypes and coronary reactivity, the development of early and advanced atherosclerotic lesions in coronary arteries, the developing risk of acute myocardial infarction (AMI) and sudden cardiac death (SCD). Furthermore, the effect of LIPC genotypes on atherosclerosis progression during long-term hormone replacement therapy (HRT) was assessed.

The study was based on six study series (studies I-VI), comprising a total of 1,282 subjects. The subjects included 49 healthy, mildly hypercholesterolemic young men (study I) and 108 (included study I subjects) young men with varying lipid statuses (study II). The first two studies evaluated the association between the LIPC genotypes and the indices of coronary blood flow as measured with positron emission tomography. Study III examined the relationship between the LIPC genotypes and autopsy-confirmed areas of different types of atherosclerotic lesions in the coronary arteries of 700 middle-aged men. In study IV, 386 men who were followed up for an average of nine years were analyzed to investigate the association between the LIPC genotypes and the risk of developing AMI. Study V elucidated the association between the LIPC genotypes and the pre-hospital SCD in 700 male autopsy subjects. In study VI, 88 postmenopausal women participated in long-term HRT to determine the effect of LIPC genotypes on the progression of atherosclerosis severity.

LIPC -480T allele carriers had lower coronary flow reserve (CFR) than the CC homozygotes (study I). In study II, T allele carriers had lower coronary flow during hyperemia, lower CFR and higher coronary resistance during hyperemia than subjects with the CC genotype among young men with different lipid statuses, and the effect was independent of the level of plasma cholesterol. In the autopsy study III, men with the TT genotype had two times larger areas of fatty streaks compared to the CC homozygotes. However, this association was only significant in men = 53 years). In the observational study VI on postmenopausal women during long-term HRT, the progression of atherosclerosis severity in subjects with the T allele was significantly faster in the control group than the HRT group, whereas there were no significant differences in atherosclerosis progression between the control and HRT groups in the CC genotype.

We conclude that the LIPC C-480T polymorphism is an important genetic marker for atherosclerosis and responds to long-term HRT during atherosclerosis progression.

Atherosclerosis is the major cause of morbidity and mortality in Western society. Atherosclerosis arises from a genetic predisposition, interacting with environmental risk factors. Hepatic lipase (HL) is a glycoprotein, functioning mainly as a lipolytic enzyme by hydrolysing triglycerides and phospholipids in almost all major classes of lipoproteins. HL maybe involved in the modulation of the risk for dyslipidemia and atherosclerosis due to its essential role in both high-density lipoprotein (HDL) and triglyceride-rich lipoprotein metabolism. The HL gene (LIPC) has a functional promoter polymorphism at position -480, which affects transcription and leads to CC, CT and TT genotypes.

To elucidate the association betweem LIPC C-480T genotypes and coronary reactivity, the development of early and advanced atherosclerotic lesions in coronary arteries, the developing risk of acute myocardial infarction (AMI) and sudden cardiac death (SCD). Furthermore, the effect of LIPC genotypes on atherosclerosis progression during long-term hormone replacement therapy (HRT) was assessed.

The study was based on six study series (studies I-VI), comprising a total of 1,282 subjects. The subjects included 49 healthy, mildly hypercholesterolemic young men (study I) and 108 (included study I subjects) young men with varying lipid statuses (study II). The first two studies evaluated the association between the LIPC genotypes and the indices of coronary blood flow as measured with positron emission tomography. Study III examined the relationship between the LIPC genotypes and autopsy-confirmed areas of different types of atherosclerotic lesions in the coronary arteries of 700 middle-aged men. In study IV, 386 men who were followed up for an average of nine years were analyzed to investigate the association between the LIPC genotypes and the risk of developing AMI. Study V elucidated the association between the LIPC genotypes and the pre-hospital SCD in 700 male autopsy subjects. In study VI, 88 postmenopausal women participated in long-term HRT to determine the effect of LIPC genotypes on the progression of atherosclerosis severity.

LIPC -480T allele carriers had lower coronary flow reserve (CFR) than the CC homozygotes (study I). In study II, T allele carriers had lower coronary flow during hyperemia, lower CFR and higher coronary resistance during hyperemia than subjects with the CC genotype among young men with different lipid statuses, and the effect was independent of the level of plasma cholesterol. In the autopsy study III, men with the TT genotype had two times larger areas of fatty streaks compared to the CC homozygotes. However, this association was only significant in men = 53 years). In the observational study VI on postmenopausal women during long-term HRT, the progression of atherosclerosis severity in subjects with the T allele was significantly faster in the control group than the HRT group, whereas there were no significant differences in atherosclerosis progression between the control and HRT groups in the CC genotype.

We conclude that the LIPC C-480T polymorphism is an important genetic marker for atherosclerosis and responds to long-term HRT during atherosclerosis progression.